Methods and means for treating DNA repeat instability associated genetic disorders

Abstract

The current invention provides for methods and medicaments that apply an oligonucleotide comprising aninosine and/or an uracile and/or a nucleotide containing a base able to form a wobble base pair, said oligonucleotide being preferably RNAse H substantially independent and being complementary only to a repetitive sequence in a human gene transcript, for the manufacture of a medicament for the diagnosis, treatment or prevention of a cis-element repeat instability associated genetic disorders in humans. The invention hence provides a method of treatment for cis-element repeat instability associated genetic disorders. The invention also pertains to a modified oligonucleotide which can be applied in a method of the invention to prevent the accumulation and/or translation of repeat expanded transcripts in cells.

1. An oligonucleotide comprising an inosine, wherein said oligonucleotide consists of a sequence that is complementary to a repetitive sequence selected from the group consisting of (CAG)n, (GCG)n, (CUG)n, (CGG)n, (GAA)n, (GCC)n and (CCUG)n, and is 9 to 50 nucleotides long. 
     
     
       2. An oligonucleotide according to  claim 1 , consisting of a sequence that is complementary to a repetitive sequence selected from the group consisting of (CAG)n, (GCG)n, (CUG)n, (CGG)n, (GAA)n, (GCC)n and (CCUG)n, wherein the oligoucleotide is 9 to 50 nucleotides long and wherein the oligonucleotide is a RNAse H substantially independent oligonucleotide. 
     
     
       3. An oligonucleotide according to  claim 1 , wherein said oligonucleotide comprises a radioactive label or fluorescent label. 
     
     
       4. An oligonucleotide according to  claim 2 , wherein said oligonucleotide comprises a radioactive label or fluorescent label. 
     
     
       5. A pharmaceutically acceptable composition comprising an oligonucleotide as defined in any one of  claims 1  to  4  and at least one excipient and/or targeting ligand for delivery of the oligonucleotide to the cell and/or enhancing the intracellular delivery of the oligonucleotide. 
     
     
       6. A nucleic acid vector capable of conferring expression of an oligonucleotide as defined by any one of  claims 1  to  4  in human cells. 
     
     
       7. An oligonucleotide according to any one of  claims 1 - 4 , wherein the oligonucleotide consists of (CIG) 7  and is a 2′-O-methyl RNA phosphorothioate oligonucleotide. 
     
     
       8. The nucleic acid vector of  claim 6 , wherein said vector is a viral vector.